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Hormonal Replacement Therapy (HRT) and Osteoporosis

General Information


  • HRT (estrogen alone or combined with progestogen or another agent [such as bazedoxifene]) is used for the prevention and treatment of osteoporosis in postmenopausal women with the goal of inhibiting bone resorption and reducing risk of osteoporotic fractures1,2,3,4
  • while HRT is associated with reduced risk of fractures in postmenopausal women, it is associated with several adverse effects; the decision to use HRT for prevention and treatment of osteoporosis should weigh benefits and risks of HRT versus nonhormone therapies and consider preferences of the individual patient1,2


Overview of Osteoporosis

  • osteoporosis is a generalized skeletal disorder characterized by1,4
    • decreased bone mass
    • microarchitectural deterioration of bone tissue
    • diminished bone strength
    • increased risk for bone fragility and fracture
      • risk of fracture reported to progressively increase with decreasing bone mineral density
      • > one-third of adult women and 1 in 5 men reported to experience ≥ 1 fragility fractures in their lifetime
      • common sites of fragility fracture include proximal femur, pelvis, vertebral bodies, distal radius, and proximal humerus
      • most major fractures reported to be associated with reduced relative survival, with the effect persisting > 5 years after the fracture event
    • Reference - United Kingdom National Osteoporosis Guideline Group clinical guideline for the prevention and treatment of osteoporosis (28425085Arch Osteoporos 2017 Dec;12(1):43full-text)
  • most commonly affects the spine, hip, and wrist4
  • worldwide prevalence of osteoporosis reported in estimated 200 million people4
  • in United States4
    • about 54 million women and men reported to have low bone density or osteoporosis
    • among individuals > 50 years old, osteoporosis reported in 16% of women and 4% of men
    • incidence of osteoporosis-related fractures reported to be > 1.5 million fractures per year, including an estimated 700,000 vertebral fractures and 300,000 hip fractures
    • Reference - cxh102126482pmdc25871674pJAMA 2015 Apr 14;313(14):1467
  • risk factors for osteoporotic fracture include (but not limited to)4
    • increasing age
    • female sex
    • postmenopause for women
    • low body weight
    • history of parental hip fracture
    • ethnic background (white persons are at more increased risk than black persons)
    • genetic conditions, such as cystic fibrosis
    • previous clinical or morphometric vertebral fracture
    • previous fracture due to minimal trauma (that is, previous osteoporotic fracture)
    • rheumatoid arthritis (RA)
    • hypogonadism or primary ovarian insufficiency
    • gastrointestinal disorders, such as malabsorption
    • current smoking
    • alcohol intake (≥ 3 drinks daily)
    • low bone mineral density
    • vitamin D deficiency
    • low calcium intake
    • hyperkyphosis
    • falling
    • immobilization
    • long-term use of certain medications, the most commonly implicated being
    • see Osteoporosis causes and risk factors for details
  • diagnosis of osteoporosis in postmenopausal women and men ≥ 50 years old includes one of the following1,4
  • bone health is a function of genetics, although it may be modified by lifestyle factors such as weight-bearing exercise, diet, and avoiding substances toxic to bone1
  • goal of treatment of osteoporosis is prevention of fracture1
  • pharmacologic treatments for osteoporosis include1,4
    • bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid) (see also Bisphosphonates for treatment and prevention of osteoporosis)
    • parathyroid hormone 1-34 (teriparatide) or parathyroid hormone related peptide (PTHrP[1-34]) analog (abaloparatide) (FDA DailyMed 2017 Sep 19)
    • estrogen (in the form of HRT) for postmenopausal women
    • selective estrogen receptor modulators (SERMs) (such as raloxifene) for postmenopausal women
    • calcitonin
    • receptor activator of nuclear factor kappa-B (RANK) inhibitor (denosumab)
    • see Medications in Osteoporosis for additional information

Overview of Menopause

  • primary ovarian insufficiency (POI) (also known as premature ovarian failure or premature menopause)1
    • defined as primary hypogonadism in women < 40 years old who have a normal karyotype and who previously had normal menstrual cycles
    • reported in 1% of women < 40 years old and in 0.1% of women < 30 years old
    • characterized by
      • typical menopausal symptoms
      • signs including amenorrhea or oligomenorrhea and follicle-stimulating hormone > 40 units/L
    • due to depletion or dysfunction of ovarian follicles from a variety of causes including
      • genetic (including fragile X premutation)
      • enzyme deficiencies
      • iatrogenic
      • autoimmune (associated with polyglandular autoimmune syndromes)
      • idiopathic resulting in depletion or dysfunction of ovarian follicles
      • Reference - Endocrine Society clinical practice guideline on treatment of symptoms of menopause (26444994J Clin Endocrinol Metab 2015 Nov;100(11):3975full-text)
  • estrogen depletion associated with menopause may cause symptoms that affect quality of life, including1,2,3
    • vasomotor symptoms (hot flushes and night sweats); 75% of postmenopausal women < 55 years old report vasomotor symptoms, with 28.5% of women reporting moderate-to-severe symptoms
    • mood swings
    • memory and concentration loss
    • vaginal dryness
    • lack of interest in sex
    • headaches
    • joint and muscle pains
    • sleep disturbances
    • genitourinary syndrome (vulvovaginal atrophy and urinary tract atrophy) and recurrent urinary tract infections
    • Reference - National Institute for Health and Care Excellence (NICE) quality standard on menopause (NICE 2017 Feb:QS143PDF)
  • menopause reported as a strong risk factor for chronic diseases such as cardiovascular disease and osteoporosis3
  • treatment1,3
    • lifestyle modification, including diet and exercise, may reduce menopausal symptoms
    • for treatment of vasomotor symptoms
      • hormone replacement therapy
      • nonhormonal therapies such as
        • selective serotonin reuptake inhibitors (SSRIs)
        • serotonin-norepinephrine reuptake inhibitors (SNRIs)
        • clonidine
        • gabapentin
        • paroxetine
      • several biologically based therapies (such as phytoestrogens [such as dietary soy isoflavones] and black cohosh [see also Black cohosh for menopausal symptoms) might reduce vasomotor symptoms, but evidence is limited
    • for treatment of urogenital symptoms
      • hormone replacement therapy
      • local estrogen therapy
      • nonestrogen water-based or silicone-based vaginal lubricants and moisturizers
    • for treatment and prevention of osteoporosis see pharmacological treatment for osteoporosis above
    • see Menopause for details

Overview of HRT

  • HRT is approved by FDA for2
  • HRT includes a wide range of hormonal products and routes of administration, including1,2,3
    • estrogens, most commonly prescribed preparations include
      • conjugated equine estrogen (CEE)
      • synthetic conjugated estrogens
      • micronized 17-beta-estradiol
      • ethinyl estradiol
    • progestogens
      • protect women with intact uteri against chronic unopposed estrogen exposure, which increases risk for endometrial hyperplasia and cancer
      • administered as either progesterone or progestin (synthetic)
      • most commonly used progestins include
        • medroxyprogesterone acetate
        • norethindrone acetate
        • native progesterone
      • in the United States, medroxyprogesterone acetate is typically used, while a variety of progestogens are used in Europe (29730442Pharmacol Ther 2018 Sep;189:123)
    • tibolone (where available)
      • synthetic steroid with estrogenic, progestogenic, and androgenic activity
      • not available in North America
    • conjugated equine estrogen/bazedoxifene
  • FDA-issued black box warning recommends estrogen (with or without progestin) should be prescribed for the shortest duration and lowest effective dose to be consistent with patient's treatment goals and risks (cxh126797798pmdc29234814pJAMA 2017 Dec 12;318(22):2224)
  • risks of HRT differ for women, depending on type, dose, duration of use, route of administration, timing of initiation, and whether a progestogen is needed2


  • menopause3
    • results from oocyte depletion and ovarian failure, leading to reduced secretion of ovarian hormones estrogen and progesterone
    • clinical manifestations result from the interactions between neuroendocrine changes and alterations in reproductive axis that governs ovarian function
    • see Menopause for additional information
  • osteoporosis1,3
    • bone is a dynamic tissue that is continuously being remodeled
      • bone remodeling begins with bone resorption (removal of old bone), which is carried out by osteoclasts (multinucleated giants cells)
      • osteoclasts create lacuna, which is filled with osteoid (new nonmineralized bone produced by osteoblasts) and later mineralized to create mature bone tissue
      • estrogens regulate coupling of bone resorption and formation processes
    • during menopause, estrogen deficiency
      • results in uncoupling of bone remodeling, from
        • increased production of cytokine receptor activator of nuclear factor-kappa B ligand (RANKL; also known as TNFSF11) by osteoblasts, resulting in osteoclast activation and increased bone resorption
        • decreased production of osteoprotegerin, an osteoblast-derived inhibitor of RANKL, further increasing RANKL activity
      • combined with age-related
        • decline in intestinal calcium absorption, vitamin D deficiency, and impaired synthesis of active 1,25-dihydroxyvitamin D by the kidney leads to secondary hyperparathyroidism, which further contributes to accelerated bone resorption
        • reduction in mechanical stimulation leads to increased sclerostin secretion by functioning osteocytes and fewer osteocyte numbers and function, resulting in a dysfunctional osteocyte-osteoblast bone formation axis and bone resorption exceeding bone formation (mnh23229466pcxh87910340pmdc23229466pOsteoporos Int 2013 Jun;24(6):1771)
      • when bone resorption exceeds bone formation, bone is only partially replaced leading to low bone mass, reduced bone strength, and increased risk of low-trauma fractures (mnh23229466pcxh87910340pmdc23229466pOsteoporos Int 2013 Jun;24(6):1771)
      • the younger a woman experiences menopause (estrogen deficiency), the greater the risk for developing osteoporosis
  • HRT
    • HRT prevents bone loss in postmenopausal women by inhibiting osteoclast-driven bone resorption and reducing rate of bone remodeling2
    • estrogens bind to 2 estrogen receptors (ER): ER-alpha and ER-beta resulting in altered gene transcriptional in target tissues (29730442Pharmacol Ther 2018 Sep;189:123)
    • progestogens prevent endometrial hyperplasia and endometrial cancer in women with a uterus by decreasing nuclear mitotic activity caused by estrogens (27548404Expert Opin Drug Saf 2016 Nov;15(11):1515)
    • selective estrogen receptor modulators (SERMs) despite lacking the estrogen steroid moiety, bind to ERs with high affinity



General References Used

  1. Baber RJ, Panay N, Fenton A, IMS Writing Group. 2016 IMS Recommendations on women's midlife health and menopause hormone therapy. Climacteric. 2016 Apr;19(2):109-50
  2. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of North American Menopause Society. Menopause. 2017 Jul;24(7):728-753
  3. Davis SR, Lambrinoudaki I, Lumsden M, et al. Menopause. Nat Rev Dis Primers. 2015 Apr 23;1:15004
  4. Qaseem A, Forciea MA, McLean RM, Denberg TD. Treatment of Low Bone Density or Osteoporosis to Prevent Fractures in Men and Women: A Clinical Practice Guideline Update from the American College of Physicians. Ann Intern Med. 2017 Jun 6;166(11):818-839, correction can be found Ann Intern Med 2017 Sep 19;167(6):448, commentary can be found in Ann Intern Med 2017 Jun 6;166(11):852

Recommendation Grading Systems Used

  • American College of Physicians (ACP) guideline grading system
    • strength of recommendation
      • Strong - benefits clearly outweigh risks and burden, or risks and burden clearly outweigh benefits
      • Weak - benefits closely balanced with risks and burden or uncertainty in estimates of benefits, risks, and burdens
      • Insufficient - balance of benefits and risks cannot be determined
    • quality of evidence
      • High - randomized trials without important limitations, or overwhelming evidence from observational studies
      • Moderate - randomized trials with important limitations (inconsistent results, methodologic flaws, indirect, or imprecise), or exceptionally strong evidence from observational studies
      • Low - observational studies or case series
      • Insufficient - evidence is conflicting, poor quality, or lacking
    • Reference - ACP guideline update on treatment of low bone density or osteoporosis to prevent fractures in men and women (mnh28492856pmdc28492856pAnn Intern Med 2017 Jun 6;166(11):818)
  • Endocrine Society uses Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) system
    • strength of recommendation
      • Strong recommendation - guideline panel members have high confidence that desirable effects of recommendation outweigh undesirable effects (or vice versa)
      • Weak recommendation - guideline panel members conclude with less confidence that desirable effects of recommendation probably outweigh undesirable effects, or benefits and harms are finely balanced, or appreciable uncertainty
    • quality of evidence
      • High-quality evidence - consistent evidence from well-performed randomized controlled trials, or exceptionally strong evidence from unbiased observational studies
      • Moderate-quality evidence - randomized controlled trials with important limitations (inconsistent results, methodological flaws, indirect or imprecise evidence), or unusually strong evidence from unbiased observational studies
      • Low-quality evidence - ≥ 1 critical outcome from observational studies, randomized controlled trials with serious flaws, or indirect evidence
      • Very low-quality evidence - ≥ 1 of the critical outcomes from unsystematic clinical observations or very indirect evidence
  • International Menopause Society (IMS) uses Royal College of Obstetricians and Gynaecologists levels of evidence and grades of recommendations
    • grades of recommendation
      • Grade A
        • ≥ 1 meta-analysis, systematic review, or randomized controlled trial rated as 1++ and directly applicable to target population, or
        • systematic review of randomized controlled trials or body of evidence consisting principally of studies rated as 1+ directly applicable to target population and demonstrating overall consistency of results
      • Grade B
        • body of evidence including studies rated as 2++ directly applicable to target population and demonstrating overall consistency of results, or
        • extrapolated evidence from studies rated as 1++ or 1+
      • Grade C
        • body of evidence including studies rated as 2+ directly applicable to target population and demonstrating overall consistency of results, or
        • extrapolated evidence from studies rated as 2++
      • Grade D
        • evidence level 3 or 4, or
        • extrapolated evidence from studies rated as 2+
      • Good practice point (GPP) - recommended best practice based on clinical experience of guideline development group
    • classification of evidence levels
      • Level 1++ - high-quality meta-analyses, systematic reviews of randomized controlled trials, or randomized controlled trials with very low risk of bias
      • Level 1+ - well-conducted meta-analyses, systematic reviews of randomized controlled trials, or randomized controlled trials with low risk of bias
      • Level 1- - meta-analyses, systematic reviews of randomized controlled trials, or randomized controlled trials with high risk of bias
      • Level 2++ - high-quality systematic reviews of case-control or cohort studies or high-quality case-control or cohort studies with very low risk of confounding, bias, or chance and high probability that relationship is causal
      • Level 2+ - well-conducted case-control or cohort studies with low risk of confounding, bias, or chance and moderate probability that relationship is causal
      • Level 2- - case-control or cohort studies with high risk of confounding, bias, or chance and significant risk that relationship is not causal
      • Level 3 - nonanalytical studies, such as case reports or case series
      • Level 4 - expert opinion
  • United Kingdom National Osteoporosis Guideline Group (NOGG) grading recommendations
    • levels of evidence
      • Level Ia - evidence from meta-analysis of randomized controlled trials
      • Level Ib - evidence from ≥ 1 randomized controlled trial
      • Level IIa - evidence from ≥ 1 well-designed nonrandomized controlled study
      • Level IIb - evidence from ≥ 1 other type of well-designed quasi-experimental study
      • Level III - evidence from well-designed nonexperimental descriptive studies, such as comparative studies, correlation studies, and case studies
      • Level IV - evidence from expert committee reports or opinions and/or clinical experiences of respected authorities
    • grades of recommendations
      • Grade A - at least 1 randomized controlled trial in body of literature of overall good quality and consistency addressing specific recommendation (evidence levels Ia and Ib)
      • Grade B - well-conducted clinical studies but no randomized clinical trials on topic of recommendation (evidence levels IIa, IIb, and III)
      • Grade C - absence of directly applicable clinical studies of good quality (evidence level IV)
    • Reference - NOGG clinical guideline for the prevention and treatment of osteoporosis (28425085Arch Osteoporos 2017 Dec;12(1):43full-text)
  • United States Preventive Services Task Force (USPSTF) grades of recommendation (June 2007 to June 2012)
    • Grade A - USPSTF recommends the service with high certainty of substantial net benefit
    • Grade B - USPSTF recommends the service with high certainty of moderate net benefit or moderate certainty of moderate-to-substantial net benefit
    • Grade C - clinicians may provide the service to select patients depending on individual circumstances; however, only small benefit is likely for most individuals without signs or symptoms
    • Grade D - USPSTF recommends against providing the service with moderate-to-high certainty of no net benefit or harms outweighing benefits
    • Grade I - insufficient evidence to assess balance of benefits and harms
    • Reference - (cxh126797798pmdc29234814pJAMA 2017 Dec 12;318(22):2224)

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